Treatment-resistant depression (TRD) represents a significant challenge in mental health, with limited efficacy from standard therapeutic interventions. This study examines the comparative efficacy of repetitive transcranial magnetic stimulation (rTMS) and a pharmacological combination of mirtazapine and venlafaxine in TRD patients in a low-resource setting. A cross-sectional study was conducted among 500 patients diagnosed with TRD at specialized centers in Pakistan. Patients were assigned to two groups: rTMS (Group A) and pharmacotherapy (Group B). The primary outcomes were changes in Hamilton Depression Rating Scale (HDRS) and Generalized Anxiety Disorder Scale (GAD-7) scores, adherence, and patient satisfaction over six weeks. Results revealed that rTMS resulted in a significantly greater reduction in HDRS (mean change: 14.2 ± 2.5) and GAD-7 (mean change: 8.5 ± 1.8) scores compared to pharmacotherapy (HDRS: 10.1 ± 2.9, GAD-7: 5.9 ± 2.1; p < 0.001). Adherence and satisfaction rates were also higher in the rTMS group. These findings underscore the potential of rTMS as a transformative intervention for TRD in resource-constrained environments, providing superior outcomes in symptom relief and adherence. This study highlights the clinical relevance of neuroscience-informed interventions and offers a foundation for future research into scalable, evidence-based solutions for underserved populations.